ADAM (A Disintegrin and Metalloprotease) is a generic name for a single transmembrane protein having two characteristic domain structures, namely, a disintegrin-like domain and a metalloprotease-like domain. In 1992, Blobel et al. succeeded in the cloning of ADAM1 (Fertilin α) and ADAM2 (Fertilin β) (Blobel C. P., Wolfsberg T. G. et al., (1992). Nature. 356: 248-252). Thereafter, their paralogs have been successively cloned. As a result, at present, it has been clarified that such ADAM genes form an enormous family consisting of approximately 30 species.
Disintegrin is a peptide having the ability to inhibit blood coagulation, which is contained in the hemolytic snake venom of Trimeresurus flavoviridis (habu), rattlesnake, etc. It has been known that disintegrin inhibits the binding of integrin αIIbβ3 to fibrinogen on a thrombocyte. The amino acid sequence of a disintegrin-like domain of the ADAM family has high homology with that of snake venom disintegrin. As a matter of fact, it has been reported that several types of ADAM proteins bind to integrin (Judith M White. (2003). Cell Biology 15: 598-606).
Another characteristic domain, metalloprotease-like domain, has high homology at the amino acid sequence level with snake venom metalloprotease or matrix metalloprotease. Thus, the metalloprotease-like domain is expected to function as a protease. In fact, it has been reported that several ADAM proteins have protease activity (D. F. Seals and S. A. Courtneidge (2003). Genes & Development 17: 7-30). However, approximately half of ADAM genes do not have a zinc-binding motif (HEXXHXXGXXH) that is considered essential for metalloprotease activity, and thus it is considered that such ADAM genes do not have protease activity.
Taking into consideration these characteristic domain structures, it is considered that the ADAM protein has two functions, namely, a function to recognize a specific integrin and a function to specifically process a substrate protein. It is considered that some ADAM proteins have both of the two functions and that the other ADAM proteins have either one function. In addition, it has been reported that such an ADAM protein is produced in the form of a precursor, and that when a Pro domain (proprotein domain) is cleaved, the ADAM protein is expressed on the surface of a cell.
To date, the full-length sequence of an ADAM11 gene belonging to the ADAM family has been determined, and it has been reported that the ADAM 11 gene is a breast cancer inhibiting gene (Japanese Patent Laid-Open Publication No. 330799/1995). Many ADAM family genes are expressed specifically in germ-line tissues, or are expressed in a wide range of tissues. In contrast, it has been confirmed that the ADAM11 gene is highly expressed specifically in nervous system tissues (Sagane K., Ohya Y, et al., (1998). Biochem J 334: 93-98). However, specific functions of the ADAM11 gene towards nervous system tissues have not been reported.